The Journal of Immunology, Vol 157, Issue 8 3290-3297, Copyright © 1996 by American Association of Immunologists

ARTICLES

Induction of activator protein (AP)-1 and nuclear factor-kappaB by CD28 stimulation involves both phosphatidylinositol 3-kinase and acidic sphingomyelinase signals

CE Edmead, YI Patel, A Wilson, G Boulougouris, ND Hall, SG Ward and DM Sansom
Bath Institute for Rheumatic Diseases and School of Pharmacy and Pharmacology, University of Bath, United Kingdom.

A major obstacle in understanding the signaling events that follow CD28 receptor ligation arises from the fact that CD28 acts as a costimulus to TCR engagement, making it difficult to assess the relative contribution of CD28 signals as distinct from those of the TCR. To overcome this problem, we have exploited the observation that activated human T cell blasts can be stimulated via the CD28 surface molecule in the absence of antigenic challenge; thus, we have been able to observe the response of normal T cells to CD28 activation in isolation. Using this system, we observed that CD28 stimulation by B7-transfected CHO cells induced a proliferative response in T cells that was not accompanied by measurable IL-2 production. However, subsequent analysis of transcription factor generation revealed that B7 stimulation induced both activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) complexes, but not NF-AT. In contrast, engagement of the TCR by class II MHC/superantigen, either with or without CD28 ligation, resulted in the induction of NF-AT, AP-1, and NF-kappaB as well as IL-2 production. Using selective inhibitors, we investigated the signaling pathways involved in the CD28-mediated induction of AP-1 and NF-kappaB. This revealed that NF-kappaB generation was sensitive to chloroquine, an inhibitor of acidic sphingomyelinase, but not to the phosphatidylinositol 3-kinase inhibitor, wortmannin. In contrast, AP-1 generation was inhibited by wortmannin and was also variably sensitive to chloroquine. These data suggest that in activated normal T cells, CD28-derived signals can stimulate proliferation at least in part via NF-kappaB and AP-1 generation, and that this response uses both acidic sphingomyelinase and phosphatidylinositol 3-kinase-linked pathways.

This article has been cited by other articles:

				N. Marquez, R. Sancho, A. Macho, M. A. Calzado, B. L. Fiebich, and E. Munoz Caffeic Acid Phenethyl Ester Inhibits T-Cell Activation by Targeting Both Nuclear Factor of Activated T-Cells and NF-{kappa}B Transcription Factors J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 993 - 1001. [Abstract] [Full Text] [PDF]

				R. Sancho, A. Macho, L. de La Vega, M. A. Calzado, B. L. Fiebich, G. Appendino, and E. Munoz Immunosuppressive Activity of Endovanilloids: N-Arachidonoyl-Dopamine Inhibits Activation of the NF-{kappa}B, NFAT, and Activator Protein 1 Signaling Pathways J. Immunol., February 15, 2004; 172(4): 2341 - 2351. [Abstract] [Full Text] [PDF]

				S. B. Han, S. H. Park, Y. J. Jeon, Y. K. Kim, H. M. Kim, and K. H. Yang Prodigiosin Blocks T Cell Activation by Inhibiting Interleukin-2Ralpha Expression and Delays Progression of Autoimmune Diabetes and Collagen-Induced Arthritis J. Pharmacol. Exp. Ther., November 1, 2001; 299(2): 415 - 425. [Abstract] [Full Text] [PDF]

				K. J. Procyk, M. R. Rippo, R. Testi, F. Hofmann, P. J. Parker, and M. Baccarini Lipopolysaccharide induces Jun N-terminal kinase activation in macrophages by a novel Cdc42/Rac-independent pathway involving sequential activation of protein kinase C zeta and phosphatidylcholine-dependent phospholipase C Blood, October 1, 2000; 96(7): 2592 - 2598. [Abstract] [Full Text] [PDF]

				P. Secchiero, D. Zella, S. Curreli, P. Mirandola, S. Capitani, R. C. Gallo, and G. Zauli Engagement of CD28 Modulates CXC Chemokine Receptor 4 Surface Expression in Both Resting and CD3-Stimulated CD4+ T Cells J. Immunol., April 15, 2000; 164(8): 4018 - 4024. [Abstract] [Full Text] [PDF]

				M. BALTZAN, S. MEHTA, T. H. KIRKHAM, and M. G. COSIO Randomized Trial of Prolonged Chloroquine Therapy in Advanced Pulmonary Sarcoidosis Am. J. Respir. Crit. Care Med., July 1, 1999; 160(1): 192 - 197. [Abstract] [Full Text]

				H.-T. Ni, M. J. Deeths, W. Li, D. L. Mueller, and M. F. Mescher Signaling Pathways Activated by Leukocyte Function-Associated Ag-1-Dependent Costimulation J. Immunol., May 1, 1999; 162(9): 5183 - 5189. [Abstract] [Full Text] [PDF]

				Z. K. Pan, S. C. Christiansen, A. Ptasznik, and B. L. Zuraw Requirement of Phosphatidylinositol 3-Kinase Activity for Bradykinin Stimulation of NF-kappa B Activation in Cultured Human Epithelial Cells J. Biol. Chem., April 9, 1999; 274(15): 9918 - 9922. [Abstract] [Full Text] [PDF]

				N. Schwarzer, R. Nost, J. Seybold, S. K. Parida, O. Fuhrmann, M. Krull, R. Schmidt, R. Newton, S. Hippenstiel, E. Domann, et al. Two Distinct Phospholipases C of Listeria monocytogenes Induce Ceramide Generation, Nuclear Factor-{kappa}B Activation, and E-Selectin Expression in Human Endothelial Cells J. Immunol., September 15, 1998; 161(6): 3010 - 3018. [Abstract] [Full Text] [PDF]